COMPANY OVERVIEW DINESH V. PATEL, PHD | PRESIDENT & CEO - FEBRUARY 2022
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Forward-looking Statements This presentation and the accompanying oral presentation contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All statements other than statements of historical facts contained in this presentation, including statements regarding our future results of operations and financial position, business strategy, product candidates, capital resources, potential markets for our product candidates, enrollment in our clinical trials, any potential impact on our business related to COVID-19, our potential receipt of milestone payments and royalties under our Collaboration Agreement with Janssen Biotech, Inc., are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potentially” “predict,” “should,” “will” or the negative of these terms or other similar expressions. The forward-looking statements made in this presentation involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. These forward-looking statements are subject to risks and uncertainties, including those discussed in Protagonist’s filings with the Securities and Exchange Commission, including in the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of most recently filed periodic reports on Form 10-K and Form 10-Q and subsequent filings and in the documents incorporated by reference therein. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified and some of which are beyond our control, you should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. Except as required by applicable law, we do not plan to publicly update or revise any forward- looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. This presentation concerns products that are under clinical investigation and which have not yet been approved for marketing by the U.S. Food and Drug Administration. They are currently limited by Federal law to investigational use, and no representation is made as to their safety or effectiveness for the purposes for which they are being investigated. The trademarks included herein are the property of the owners thereof and are used for reference purposes only. Such use should not be construed as an endorsement of such products. Nothing contained in this presentation is, or should be construed as, a recommendation, promise or representation by the presenter or Protagonist or any director, employee, agent or advisor of Protagonist. This presentation does not purport to be all inclusive or to contain all the information you may desire. 2
Protagonist Therapeutics Peptide-based Medicines Discovering novel peptide therapeutics through a proprietary technology platform and developing them to address unmet medical needs in both rare and common diseases POTENCY 1 Computational 3 Vectrix, Clusters 2 Peptide Chemistry CLINICAL ASSETS SAR, Leads Phage Libraries Hits Rusfertide Vectrix ® Clusters PN-943 STABILITY PN-235 4 6 Systemic Availability Oral Stability 5 Formulation Peptidomimetics GI-Restricted SAR, Transport GI Assays Targeted GI absorption & delivery 3
Product Portfolio Addressing Unmet Needs in Multiple Indications with Multi-billion Dollar Market Potential PROGRAMS CANDIDATE STUDY PHASE 1 PHASE 2 Key Milestones HEMATOLOGY & BLOOD DISORDERS VERIFY PV Ph3 Polycythemia Vera (PV) Ph3 initiation 300-11 • Initiation in Q1 2022 REVIVE PV Ph2 PoC • Resuming enrollment rusfertide 300-04 • Data updates at EHA & ASH 2021 Hepcidin (PTG-300) Mimetic s.c. PACIFIC PV Ph2 in Patients with Elevated Hematocrit • Dosing resumed into OLE 300-08 • Data presented at ASH 2021 • Clinical PoC established 300-06 Hereditary Hemochromatosis (HH) Ph2 PoC • Data presented at ASH 2021 INFLAMMATORY & IMMUNOMODULATORY DISEASES Oral GI Restricted • 150 patient study a4b7-Integrin PN-943 IDEAL Ulcerative Colitis (UC) Ph2 PoC • Enrollment complete Antagonist • Topline data Q2 2022 Plaque Psoriasis Ph2 Oral • 240 patient study initiated Q1 2022 IL-23R PN-235 FRONTIER 1 Plaque Psoriasis Ph2b PoC initiation Antagonist IBD Ph2 • Initiation in 2H 2022 4
Rusfertide (PTG-300): Hepcidin Mimetic To Potentially Address Unmet Needs in Both Rare & Common Diseases 5
Polycythemia Vera Disease Background Myeloproliferative neoplasm characterized by excessive production of red blood cells (RBCs) Treatment goal • Characterized by Janus Kinase 2 (JAK2) mutation is to control hematocrit level
Rusfertide for Polycythemia Vera Overview of Current Status and Recent Progress Continued Progress Underway • Orphan, Fast Track and Breakthrough designations • Clinical update presented at ASH 2021 • Updated IB and ICF, enhanced safety surveillance measures and inclusion/exclusion criteria following brief (21-day) clinical hold. Enrollment and dosing have resumed. • Clinical studies − Phase 2 REVIVE randomized withdrawal study has resumed enrollment; data updates provided at EHA and ASH 2021 − Phase 2 PACIFIC PV study with elevated hematocrit (48% or higher) has resumed dosing into open-label extension; data presented at ASH 2021 − Regulatory interactions continue to finalize and enable Phase 3 PERSIST study initiation in Q1 2022; Phase 3 design presented at ASH 2021 Rusfertide (PTG-300) • Potential for managing hematocrit per NCCN guidelines without creating iron deficiency, while improving symptoms • Close consultation underway with regulators • Natural hormone mimetic therapy for PV 7
Polycythemia Vera Current Treatment Options Hydroxyurea Besremi* Phlebotomy +/- Phlebotomy (ropeginterferon Jakafi alfa-2b-njft injection) • Treatment goal is to maintain HCT ≤ 45% • Recommended when HCT cannot be • Approved for HU resistant/intolerant • HCT control may be erratic with up and controlled, or in high-risk patients patients down excursions from 45% • Potential long-term side effects • ~5,300 patients/yr treated** • Can lead to iron deficiency • Some patients reluctant to use • ~25% develop intolerance or resistance chemotherapeutic agents • Potential side effects include cytopenia CHRONIC TREATMENT OVER ~20 YEARS *Newly FDA approved, undergoing U.S. commercial launch; uncertain place in the therapeutic paradigm at present **Represents patients treated with Jakafi; uncertain of Besremi population due to recent approval 1. MPN Landmark Survey 2017, Trinity Primary Research 2019 8
Understanding PV Patient Journey Evaluating the Unmet Need of PV Patients in US Real world PV patient treatment data (2018-2019)1 • Evaluation of 28,306 PV patients treated in 2018-2019 • Hematocrit levels: lab tests of 4,264 patients Treated PV Patients N = 28,306 Key Findings in three categories >2 HCT Lab Tests Treatment Hematocrit Thrombotic risks N= 4,264 patterns management to and events NCCN guidelines Representative of treated PV population 1 Symphony Patient Journey Data Large, representative, and longitudinal source of healthcare claims data that captures over 290MM patients with over 78% of all prescription claims and 60% of all medical claims. Medical, hospital, and prescription history is captured across treatment settings and payers with history back to 2003 9
Real World PV Patient Treatment Data Evaluation of 28,306 PV Patients Treated in 2018-19 • Predominant treatment is phlebotomy, regardless of risk • Hydroxyurea is the most commonly used cytoreductive agent Treatment • Combination of hydroxyurea and phlebotomy commonly used to control HCT patterns • Hematocrit not managed to NCCN guidelines, Only 22% patients had all HCT tests
Rusfertide: Mechanistic Rationale for Potential Treatment of PV Polycythemia Vera MOA of rusfertide FERROPORTIN transports iron RUSFERTIDE Elevated Normalized Hematocrit Hematocrit Splenic FERROPORTIN macrophage RBC PRODUCTION HEPCIDIN EXCESSIVE RBC PRODUCTION Inhibits ferroportin 45% 45% SERUM IRON serum iron Transferrin delivers iron IRON DELIVERY 11
Phase 2 Study of Rusfertide in PV Patients (REVIVE) GOAL: Maintain Hematocrit
Effect of Rusfertide on Phlebotomy Frequency in REVIVE Study Phlebotomy only (N=31, 49%) Phlebotomy + cytoreductive (N=32, 51%) Pre-Treatment Treatment Open Label Extension (OLE) Pre-Treatment Treatment Open Label Extension (OLE) -28 to 0 weeks 28 weeks 52 weeks -28 to 0 weeks 28 weeks 52 weeks Randomization Randomization p< 0.001 p< 0.001 Screening Part 1 – Dose Finding Part 2– Blinded Withdrawal Part 3 – Open Label Extension Phlebotomy Last dose on study Data as of September 30, 2021 13
Baseline Characteristics of Study Participants in REVIVE Study Characteristics (n = 63) AGE THERAPIES Range 27-76 years (Mean = 56.3 yrs) PHL only 31 (49.2%) GENDER PHL + HU 18 (28.6%) Females 18 (28.8%) PHL + IFN 8 (12.7%) Males 45 (71.4%) PHL + RUX 3 (4.8%) RISK PHL +Multiple Agents 3 (4.8%) Low 28 (44.4%) NUMBER OF PHL IN 28 WEEKS PRIOR 35 (55.6%) High [Age based – 36.5%, Thrombotic events – 19.0%] 2-3 15 (23.8%) DURATION SINCE PV DIAGNOSIS 4-5 33 (52.3%)
Rusfertide Controls HCT and Ferritin in REVIVE Study Hematocrit Ferritin Screening Part 1 – Dose Finding Part 2/3 – Blinded Withdrawal/OLE Part 3 – Open Label Extension Box whiskers extend up to 1.5 times interquartile range. Data as of September 30, 2021 15
Improvement in MPN-TSS Scores Following Rusfertide in REVIVE Study Problems with Concentration 2.0 1.9 Total Symptom Score 1.5 Paried Mean 20 1.0 0.9 16.3 15.2 14.6 0.5 15 11.4 0.0 10 Baseline Week 28 N=24 N=24 5 Worst Level of Fatigue Itching-Pruritus 4 2.5 2.3 3.2 0 3 2.7 2.0 Baseline Week 8 Week 16 Week 28 1.6 N=62 N=56 N=50 N=24 Paired Mean 1.5 Paired Mean 2 1.0 1 0.5 0 0.0 Baseline Week 28 Baseline Week 28 N=24 N=24 N=24 N=24 Data as of September 30, 2021 16
Adverse Events Experienced on Rusfertide in REVIVE Study System Organ Class. - Preferred term AE n (%) • Most Drug related AEs were Grade 1 or 2 Total number of Subjects 63 • No Grade 4 or 5 Events No. of subjects with treatment-emergent AE 55 (87) Blood and Lymphatic Disorders 12 (19.0) • SAE’s: Syncope, peripheral artery aneurism, gastroenteritis, chest pain, AML, squamous cell Anemia 9 (14.3) carcinoma (skin), melanoma & basal cell Gastrointestinal disorders 20 (31.7) carcinoma Nausea 8 (12.7) • Injection site reaction (ISRs) were most common Infections and infestations 11 (17.5) and associated with 28.1% of injections. All ISRs Metabolism and nutrition disorders 9 (14.3) were transient, and no patient discontinued due Musculoskeletal and connective tissue disorders 27 (42.9) to ISR. Nervous system disorders 21 (33.3) • One subject stopped treatment due to AE within Psychiatric disorders 7 (11.1) 2 weeks (asymptomatic thrombocytosis) Insomnia 4 (6.3) • No clinically significant laboratory abnormalities. Renal and urinary disorders 5 (7.9) • No Anti Drug Antibody response was noted in Respiratory 14 (22.2) any patient Skin and subcutaneous tissue disorders 23 (36.5) Pruritis 9 (14.3) Data as of September 30, 2021 17
Conclusions from Phase 2 REVIVE Study Rusfertide therapy resulted in rapid, sustained and durable hematocrit control without clinically meaningful changes in white blood cell and platelet counts Rusfertide demonstrated similar efficacy in all categories of patients, independent of the PV patient risk category or concurrent therapy with hydroxyurea, interferon or ruxolitinib Subjects have been treated up to 1.5 years with subjects remaining essentially phlebotomy-free Benefits from rusfertide treatment were noted in patient reported outcomes as assessed by MPN-SAF Total Symptom Score Results to date suggest that rusfertide is well tolerated; the most common adverse events were grade 1 or 2 18
PACIFIC: Open-Label Phase 2 PV Study in Subjects with high hematocrit (>48%) Patient met the WHO criteria for PV diagnosis and had a baseline hematocrit (HCT) >48%, and a history of ≥3 HCT values >48% in the prior year prior All adult males or females with both high-risk and low-risk criteria treated with phlebotomy alone or with concurrent cytoreductive therapy were enrolled Initial dose: (40 mg SQ twice weekly). After hematocrit was
PACIFIC Phase 2 Study (High Hematocrit) Therapeutic Phlebotomies Prior to and on Rusfertide Age/Sex First Dose 005 52/F 004 47/M 006 69/F 007 62/M 011 41/M 008 70/M 009 60/M 001 49/F Subjects 003 63/M 015 53/F 018 55/M 016 58/M 014 57/M 002 46/M 019 53/M 013 63/M 012 41/M 020 56/M 017 72/F 010 66/M -52 -48 -44 -40 -36 -32 -28 -24 -20 -16 -12 -8 -4 0 4 8 12 16 20 24 28 32 36 40 Weeks Screening PTG-300 Dose decision Phlebotomy Data as of September 30, 2021 20
Rusfertide Controls HCT and Reduces RBC Count in PACIFIC Study Rusfertide Rapidly Controls HCT Rusfertide Rapidly Reduces RBC Count 8 7 RBC (10^6/uL) 6 HCT (%) 5 4 3 N 20 18 17 13 11 9 4 3 Baseline Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24 Wk 28 Weeks Weeks Screening PTG-300 Mean Screening PTG-300 Mean Data as of September 30, 2021 21
Adverse Events in Ongoing PACIFIC Study System Organ Class All AEs Preferred term n (%) Total number of Subjects 20 No. of subjects with treatment-emergent AE 16 (80.0) Blood and Lymphatic System 3 ( 15.0) • Most Drug related AEs were Grade 1 or 2 Thrombocytosis 3 ( 15.0) General disorders and Administration Site Conditions 10 (50.0) • One subject stopped treatment due to AE Injection Site Erythema 9 (45.0) (Thrombocytosis without bleeding or Injection Site Induration 5 (25.0) thrombosis; Grade 4 according to Injection Site Pruritus 2 (10.0) investigator) Injection Site Swelling 5 (25.0) • Injection site reaction (ISRs) were most Pyrexia 2 (10.0) common and associated with 68% of Nervous system disorders 5 (25.0) injections. All ISRs were transient, and no Headache 2 (10.0) patient discontinued due to ISR. Skin and subcutaneous tissue disorders 5 (25.0) Erythema 4 (20.0) • No anti-drug antibody response was noted in Pruritus 4 (20.0) any patient Vascular disorders 2 (10.0) Hypertension 2 (10.0) Data as of September 30, 2021 22
Conclusions from PACIFIC High Hematocrit Study Rusfertide induction therapy with twice weekly dosing is effective at rapidly achieving target hematocrit below 45% without phlebotomy in all PV patients. Rapid hematocrit control:
Rusfertide Phase 3 PV Study Design (VERIFY Study) Enrollment Criteria, Primary Endpoint, Key Secondary Endpoints, Additional Assessments Enrollment Criteria: Primary Endpoint: • Adult patients with PV per 2016 WHO Criteria • Absence of phlebotomy eligibility based on • High risk and low risk patients hematocrit control between weeks 20-32 • Patients requiring frequent phlebotomy • With or without cytoreductive therapy • Exclusion of patients with invasive cancer in prior 5 years Additional Assessments: • Durability of response weeks 32-52 Key Secondary Endpoints: • Open-label treatment to evaluate long-term • Number of phlebotomies effects and safety • Symptom improvement scores • Safety The Phase 3 study design capitalizes on the successful outcome of the 60-plus patient open-label Phase 2 REVIVE Study 24
Randomized, Double-blind, Placebo-Controlled Phase 3 PV Study (VERIFY) VERIFY Study of N~250 subjects Part 1a Part 1b Part 2 Screening Double Blind (Weeks 0-32) Safety (Up to 4 Durability of Response Long Term Safety Follow-up Follow-up W eeks) Dose Titration Primary Efficacy (Weeks 32-52) (Weeks 52-156) (4 W eeks) (Weeks 0-20) (Weeks 20-32) NDA + MAA filings Rusfertide + Ongoing Therapy (n=125) Screening Rusfertide + PV Therapy + Rusfertide Placebo + Ongoing Therapy Ongoing Therapy (n=125) Week 32 Week 52 Week 156 Week 0 Primary Endpoint Durability of End of Randomize Analysis (Unblind) Response Treatment (1:1) The Phase 3 study design capitalizes on the successful outcome of the 60-plus patient open-label Phase 2 REVIVE Study 25
PV Commercial Opportunity & Rusfertide Positioning LOW BURDEN MODERATE BURDEN HIGH BURDEN MF/AML (
Rusfertide Market Preparation: PV Indication Intend to Demonstrate Clinical & Economic Value Before Approval Value Distribution Market HEOR Prescriber Competitive Positioning Proposition Channels Access Education Landscape Strategy Patients Patient access Pricing & Health Economics & Raise awareness of Existing and future Leader in the Reimbursement Outcomes Research PV, unmet need and treatments treatment of PV Prescribers Strategy for assessing NCCN Guidelines Payers economic burden and benefit of treatment 27
Hereditary Hemochromatosis (HH) Disease Prevalence and Treatment HH is predominately due to genetic mutation, leading to a deficiency of hepcidin in the body Rusfertide, if approved, could serve as a hormone replacement therapy Excessive iron Phlebotomy is the Iron Unmet medical accumulation in only therapeutic overload need in specific heart, liver, option; no disease subpopulations pancreas, skin, approved drugs joint tissues If untreated, iron overload can cause hepatomegaly, diabetes mellitus, skin hyperpigmentation, cardiomyopathy, diastolic dysfunction, heart failure, cirrhosis, etc. Source: Porter JL, Rawla P. Hemochromatosis. (Updated 2020 Jun 18], https://www.ncbi.nlm.nih.gov/books/NBK430862/ 28
Proof of Concept Phase 2 Study in Hereditary Hemochromatosis SCREENING MONTH 1 MONTH 2 MONTH 3 MONTH 4 MONTH 5 MONTH 6 Pre-study Phlebotomy and Liver MRI Adverse event monitoring, dose adjustment, PK and PD (iron parameters) • Six-month, open-label study in 16 HH patients in maintenance phase of iron depletion • Stable pre-study phlebotomy for ≥6 months; requiring ≥3 phlebotomies/12 months or ≥4 phlebotomies/15 months • Patients with end-organ damage or on chelation therapy or erythrocytapheresis were excluded • Self-administered SC doses once or twice weekly • Dose adjusted to maintain serum iron & TSAT
Hereditary Hemochromatosis Summary of Results in HH and Next Steps • Significantly reduction in number • Maintained liver iron • Lowered serum iron and TSAT of phlebotomies content N=14 N=16 0.6
PN-943 and IL-23 Receptor Antagonists Oral Targeted Investigational Therapies for IBD and non-IBD indications 31
IBD: Paradigm Shift Toward Targeted Oral and Combination Therapy A growing multi-billion dollar market 2019: ~ $14B sales1 2029: projected ~ $24B sales 1 Historical IBD Treatment Paradigm Emerging IBD Treatment Paradigm Injectable mAbs with safer MOAs • α4β7 integrin: Entyvio® (~ $4B sales 2020) • IL-12/IL-23: e.g., Stelara® TNF mAbs dominated IBD Therapy Potential Oral Targeted Therapy for IBD Future of • Injectable TNF mAbs – Blockbusters Protagonist: mAb Validated Pathways IBD – Humira® & Remicade® Oral Combo • Significant room for improvement • PN-9432 (α4β7 integrin) Therapy – Low response rates / loss of response • IL-23Rs – Safety concerns - black box warnings Other Oral Approaches: New Targets • S1P1: e.g., Zeposia® • JAK*: e.g., Xeljanz®, Rinvoq® *black box warnings 1 GlobalData: Global Drug Forecast and Market Analysis to 2029; 7 Major Markets: US, EU5, JP 2 Investigational product candidate, not approved 32
Oral, Gut-Restricted, a4b7-Integrin Peptide Antagonists: PN-943 Fully Owned and Validated Asset and Approach Clinically Validated, IBD Specific Target • T cell homing regulated by α4β7 integrin and MAdCAM-1 interaction • MAdCAM-1 expressed only in GI vasculature • Entyvio (Vedolizumab) approved for Crohn’s & UC – ~$5B fiscal 2021 sales • Superior efficacy for Entyvio vs. Humira in 52 wk Ph3B VARSITY study Briskin M, et al Am J Pathol. 1997;151:97-110 PN-943: Validated, Gut-restricted Approach • First-in-class potential as an oral, GI-restricted α4β7-specific antagonist • PN-943 is ~3x more potent in numerous pre-clinical studies & Ph1 NHV study vs 1st generation candidate PTG-100 (DDW, 2019)1 – PTG-100 showed signals of clinical efficacy in Ph2a UC trial (Gastroenterology, 2021)2 Vs. • PN-943 global Ph2 150 patient study in UC patients in progress • Study completion anticipated 2Q 2022* 1Mattheakis, 2Sandborn, W. J., Mattheakis, L. C., Modi, N. B., Pugatch, D., Bressler, B., Lee, S., ... & Gupta, L., Tang, T., Venkataraman, S., Rao, N., Wang, L., Zhao, L., ... & Liu, D. Y. (2019). The oral α4β7 integrin specific antagonist PN‐10943 is more effective than S. (2021). PTG-100, an oral α4β7 antagonist peptide: preclinical development and phase 1 and 33 PTG‐100 in multiple preclinical studies. Gastroenterology, 156(Suppl 6), S80-S81. 2a studies in ulcerative colitis. Gastroenterology, 161(6), 1853-1864.
PN-943: First-in-Class Oral a4b7 Integrin Antagonist PN-943 superior to first generation PTG-100 • In vitro potency and binding kinetics with similar robust selectivity • Blood PD effects of local target engagement in 3 species with oral stability and limited blood exposure • Efficacy in rodent colitis model PN-943 was advanced into clinical development in 2019 • Oral GI-restricted approach validated by PTG-100 PROPEL Ph2a data Future Potential Assessed in Surveys with Gastroenterologists • MEDACorp 2020: “oral anti-integrins were found to be the most exciting unapproved drug class in UC” • COWEN 2020: The most exciting agent (among 10) in development for moderate-severe IBD was Protagonist’s PN-943, tied with PTG-200 34
PN-943 vs. PTG-100: Blood %RO based Clinical Proof-of-Concept Ph1 NHV Single Ascending Dose Study PTG-100 Ph2 UC PoC PN-943 vs PTG-100 Ph1 Data Ph2A Study PTG-100 Ph1 SAD Ph1 MAD, Day 14 UC 900 mg 44% 96% Histologic Remission 94% 100 83% 100 (7/16) 74% 80% 74% 16% 80 80 Maximum %RO 74% Maximum %RO Clinical Remission* 74% (3/19) 60 60 40 40 Ph 1 Study PTG-100 20 20 NHVs 1000 mg 0 0 100 mg 300 mg 1000 mg 100 mg 300 mg 1000 mg % Blood RO 74% *based on blinded endoscopic re-reads PTG-100 PN-943 * Clinical remission: SFS ≤1, RBS = 0, ESS ≤1 PN-943 vs. PTG-100 Ph1 NHV study Established 74% blood RO in healthy subjects as a translational benchmark • Higher effect on blood %RO confirms ~3x superiority of PN-943 vs. PTG-100 – PN-943 300mg blood %RO > PTG-100 1000 mg blood %RO effect • Saturable target engagement at 1000 mg QD dose Modi, N. B., Cheng, X., Mattheakis, L., Hwang, C. C., Nawabi, R., Liu, D., & Gupta, S. (2021). Single‐and Multiple‐Dose Pharmacokinetics and Pharmacodynamics of PN‐943, a Gastrointestinal‐Restricted Oral Peptide Antagonist of α4β7, in Healthy Volunteers. Clinical pharmacology in drug development. 35
PTG-100 Ph2A Efficacy Similar to Other IBD Targeted Therapy Drugs Oral/JAK Oral/S1P1 Injectable Injectable a4b7 integrin 20 a4b7/aEb7 MAdCAM Injectable Oral 18 17.6 16.9 15.8 16 15.2 15.3 15.3 % Patients in Clinical Remission 14 12.3 12 11.6 11.5 11 10 9.6 Active 9 Placebo 8 Delta 6 6.2 6 5.4 4.8 4 2.7 2 0 0 N= 905 234 132 65 81 43 284 73 225 149 19 21 Tofacitinib Ozanimod Etrolizumab SHF-647* Entyvio PTG-100 900 mg q.d. *Anti-MadCam mAb * No central read endoscopy (Entyvio) 36
IDEAL: PN-943 Phase 2 UC Study Adult Patients with UC N≈150 Part-1: Induction Part-2: Extended Treatment Period Eligibility: Active Drug 450 mg BID (n=50) • Moderate – Severe UC • 3-Component Mayo Score 5-9 points Randomize Inclusion: (n=150) Active Drug 150 mg BID (n=50) PN-943 • Bio-naïve and bio-experienced patients Placebo BID (n=50) Primary endpoint: • Clinical Remission at Week 12 Secondary endpoints: 5 weeks 12 weeks 40 Weeks Week 52 • Endoscopic, histopath, mucosal Exploratory endpoints: • Blood %RO, FCP Enrollment is complete Study completion and preliminary data readout anticipated in Q2 2022 37
The Outcome of Phase 2 IDEAL study will Inform Phase 3 decisions • Phase 2 data in UC with various candidates spanning different mechanism of actions – Large confidence intervals, influenced by study design, duration, size, demographics, & criteria – Phase 2 outcomes has generally predicted efficacy in Phase 3 Translating HHistorical Ph2, Ph3, and Approval Data in UC 2 ➞ Phase 3 ➞ Approval* Clinical Remission Delta Candidate MoA Approval Phase 2 Phase 3 Vedolizumab (Entyvio®)1 a4b7 integrin 19% 11.5% ✓ Ozanimod (Zeposia®)2 S1P 10% 12.4% ✓ Upadacitinib (Rinvoq®)3 JAK 19.6% 21/29.5% TBD (✓ RA; black box) *Cross trial comparisons complicated by different inclusion criteria, patient populations, primary endpoint definitions, timing of primary endpoint, phase of clinical development • Phase 2 data will provide specific guidance for phase 3 program on – Dose selection – Powering of registrational primary and secondary endpoints 1. Feagan, B. G., Greenberg, G. R., Wild, G., Fedorak, R. N., Paré, P., McDonald, J. W., ... & Vandervoort, M. K. (2005). Treatment of ulcerative colitis with a humanized antibody to the α4β7 integrin. New England Journal of Medicine, 352(24), 2499- 2507; Feagan, B. G., Rutgeerts, P., Sands, B. E., Hanauer, S., Colombel, J. F., Sandborn, W. J., ... & Parikh, A. (2013). Vedolizumab as induction and maintenance therapy for ulcerative colitis. New England Journal of Medicine, 369(8), 699-710. 2. Sandborn, W. J., Feagan, B. G., Wolf, D. C., D’Haens, G., Vermeire, S., Hanauer, S. B., ... & Olson, A. (2016). Ozanimod induction and maintenance treatment for ulcerative colitis. New England Journal of Medicine, 374(18), 1754-1762; Sandborn, W. J., Feagan, B. G., D’Haens, G., Wolf, D. C., Jovanovic, I., Hanauer, S. B., ... & Danese, S. (2021). Ozanimod as induction and maintenance therapy for ulcerative colitis. New England Journal of Medicine, 385(14), 1280-1291. 3. Danese, S., Vermeire, S., Zhou, W., Pangan, A., Siffledeen, J., Hébuterne, X., ... & Pannaccione, R. (2021). OP24 Efficacy and safety of upadacitinib induction therapy in patients with Moderately to Severely Active Ulcerative Colitis: Results from the phase 3 U-ACHIEVE study. Journal of Crohn's and Colitis, 15(Supplement_1), S022-S024.; Vermeire, S., Danese, S., Zhou, W., Pangan, A., Greenbloom, S., D’Haens, G., ... & Panaccione, R. (2021). OP23 Efficacy and safety of upadacitinib as induction therapy in patients with Moderately to Severely Active Ulcerative Colitis: Results from phase 3 U-ACCOMPLISH study. Journal of Crohn's & Colitis, 15(Suppl 1), S021. 38
Oral, IL-23 Receptor Specific Peptide Antagonist: PN-235 Janssen Partnership p19 antibody: Stelara®: Blocks both Objective Blocks IL-23 pathway IL-23 & IL-12 pathways • Extend the Stelara® franchise and transition from injectable to oral p19 p40 p35 p40 targeted therapy IL-23R Antagonist: Blocks IL-23 receptor – Stelara approved for psoriasis, psoriatic arthritis, Crohn’s, UC & IL-23 pathway IL-12Rβ1 IL-12Rβ1 IL-12Rβ2 IL-23R Terms CELL MEMBRANE • May 2017: Partnership initiated • $87.5M in upfront and development milestones received to date IL-23 IL-12 • Eligible for about additional $900M in milestones, up to double digit royalties, US co-detailing rights − Study initiation milestones: $25M (psoriasis) and $10M (IBD) Status Stelara® is a key Janssen franchise • Focus on the PN-235 candidate, with its superior potency and PK/PD • ~$7.7B total global sales in 2020 profile, for IBD and non-IBD indications – PN-235 (JNJ-77242113): Ph1 completed in 2021; advancing in psoriasis indication in FRONTIER 1 study, initiated in early 2022, and Vs. in IBD indications in 2H 2022 39
Janssen FRONTIER 1 Phase 2b Plaque Psoriasis (PsO) Study Screening Treatment Safety Follow-up Week 156 Adult Patients with PP End of (Up to 4 Weeks)* (Weeks 0-16) (4 Weeks) N≈240 Treatment Eligibility: Dose 1 QD • Moderate – Severe PP PN-943 Inclusion: Dose 2 QD • BSA > 10% Randomize • PASI > 12 Dose 3 QD Primary endpoint: Safety Follow-up • PASI > 75 at Week 16 Dose 1 BID Dose 3 BID Placebo Week 0 Week 16 Randomize Primary Endpoint $25M milestone payment when third patient is dosed 40
PROTAGONIST THERAPEUTICS Protagonist Team and Financials 41 41
Protagonist Team Experience & Expertise in Drug Discovery, Clinical Development, and Commercialization Dinesh Patel, PhD President & CEO David Liu, PhD CSO, Head of Discovery & Pre-Clinical Dev Samuel Saks, MD Clinical Development Advisor Suneel Gupta, PhD Chief Development Officer Donald Kalkofen Chief Financial Officer Tracy Woody EVP, Commercial Strategy Matthew Gosling, JD EVP, General Counsel Mohammad Masjedizadeh, PhD EVP, Chief Technical Officer Scott Plevy, MD EVP & Therapeutic Head, Gastroenterology Ashok Bhandari, PhD SVP, Discovery Chem & Process Res Paula O’Connor, MD SVP, Clinical Development Abha Bommireddi, MS SVP, Program Management Carter King, MBA SVP, Business Development Nishit Modi. PhD, MBA SVP, Clinical Pharmacology Sarita Khanna, PhD SVP, Biometrics 42
Financial Highlights Financial resources forecast extends through full year 2024 $352.5M 2024 47.7M CASH & SECURITIES CASH & SECURITIES SHARES OUTSTANDING As of September 30, 2021 provide financial resources as of September 30, 2021 forecast through full year 2024* *This includes our initial CMC investments in preparation for a phase 3 with PN-943 in UC, should we achieve positive Phase 2 results, we will be in a position to share more on any next steps after the data read out for PN-943 in Q2 2022 43
Upcoming Catalysts in 2022 and Beyond Significant opportunities to unlock and capture value in the 12-24 months ahead Anticipated Events of 2022 Products 2023 Q1 Q2 Q3 Q4 Rusfertide • VERIFY: Ph3 250 patient • Ph3 enrollment 1 PV study initiation ASH completion (1H) • REVIVE: Ph2 PV study EHA • Ph2 randomization 2 (300-04) continuation results (Q1) 3 • 2nd indication: HH market opportunity and next steps PN-943 • IDEAL: Ph2 150 • Ph3 UC study 4 patient UC study initiation* topline results *assuming positive Ph2 data PN-235 • Ph2 initiation – Plaque • Ph2 plaque psoriasis 5 psoriasis 6 • Ph2 initiation in IBD (2H) study results • $25M milestone • $10M milestone 7 Discovery • Nomination of oral hepcidin mimetic candidate 8 Pre-Clinical • Nomination of new development candidate – new target for new indication(s) 44
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